Particulate matter 2.5 triggers airway inflammation and bronchial hyperresponsiveness in mice by activating the SIRT2--p65 pathway

doi:10.1007/s11684-021-0839-4

Front. Med.

2021, Vol. 15

Issue (5) : 750-766 https://doi.org/10.1007/s11684-021-0839-4

RESEARCH ARTICLE

Particulate matter 2.5 triggers airway inflammation and bronchial hyperresponsiveness in mice by activating the SIRT2--p65 pathway

Manling Liu¹, Zhaoling Shi², Yue Yin¹, Yishi Wang¹, Nan Mu¹, Chen Li¹(

), Heng Ma¹(

), Qiong Wang³(

)

¹. Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi’an 710032, China
². Department of Pediatrics, Second Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712046, China
³. Department of Cardiovascular Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China

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Abstract

Exposure to particulate matter 2.5 (PM2.5) potentially triggers airway inflammation by activating nuclear factor-κB (NF-κB). Sirtuin 2 (SIRT2) is a key modulator in inflammation. However, the function and specific mechanisms of SIRT2 in PM2.5-induced airway inflammation are largely understudied. Therefore, this work investigated the mechanisms of SIRT2 in regulating the phosphorylation and acetylation of p65 influenced by PM2.5-induced airway inflammation and bronchial hyperresponsiveness. Results revealed that PM2.5 exposure lowered the expression and activity of SIRT2 in bronchial tissues. Subsequently, SIRT2 impairment promoted the phosphorylation and acetylation of p65 and activated the NF-κB signaling pathway. The activation of p65 triggered airway inflammation, increment of mucus secretion by goblet cells, and acceleration of tracheal stenosis. Meanwhile, p65 phosphorylation and acetylation, airway inflammation, and bronchial hyperresponsiveness were deteriorated in SIRT2 knockout mice exposed to PM2.5. Triptolide (a specific p65 inhibitor) reversed p65 activation and ameliorated PM2.5-induced airway inflammation and bronchial hyperresponsiveness. Our findings provide novel insights into the molecular mechanisms underlying the toxicity of PM2.5 exposure. Triptolide inhibition of p65 phosphorylation and acetylation could be an effective therapeutic approach in averting PM2.5-induced airway inflammation and bronchial hyperresponsiveness.

Keywords particulate matter 2.5 sirtuin 2 p65 airway inflammation bronchial hyperresponsiveness triptolide

Corresponding Author(s): Chen Li,Heng Ma,Qiong Wang

Just Accepted Date: 14 April 2021 Online First Date: 13 July 2021 Issue Date: 01 November 2021

Cite this article:

Manling Liu,Zhaoling Shi,Yue Yin, et al. Particulate matter 2.5 triggers airway inflammation and bronchial hyperresponsiveness in mice by activating the SIRT2--p65 pathway[J]. Front. Med., 2021, 15(5): 750-766.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0839-4
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I5/750

Fig.1 Size distribution and mass fraction of major chemical components in PM2.5. (A) SEM images of PM2.5. (B) The size distribution of PM2.5 was detected by dynamic light scattering. The median diameter of PM2.5 particles was 0.17±0.09 µm (mean±SD), and the sizes ranged from 0.03 µm to 3 µm. (C) Composition and quantity of major chemical components in PM2.5: organic carbon (OC) and elemental carbon (EC), water-soluble inorganic ions, inorganic elements, and polycyclic aromatic hydrocarbons (PAHs).

Fig.2 PM2.5 exposure induces airway inflammation and airway hyperresponsiveness. (A) Histologic analysis of the lung sections was performed with HE staining to visualize inflammatory cell recruitment. (B) The goblet cells of bronchial mucosa were stained by PAS. (C, D) Quantification of the inflammation score and the proportion of goblet cells was performed using Image-Pro Plus 6.0 software. (E) After exposure to PM2.5, the bronchial hyperresponsiveness to acetylcholine was monitored for 30 min using a Buxco system. Enhanced pause (Penh, an index of bronchoconstriction) was calculated as follows: Penh= Pause × (PEF/PIF), where Pause= (Te–Tr)/Tr (PIF, peak inspiratory flow; PEF, peak expiratory flow; Te, expiratory time; Tr, relaxation time). (F–H) The BALF was prepared and centrifuged at 450× g for 10 min. The total cell number, eosinophil, and neutrophil infiltration in BALF were determined as an indication of potential airway inflammation injury. (I–L) The levels of IL-4, IL-5, IL-6, and TNF-α in BALF were assessed by ELISA. Data are expressed as mean±SD. n = 6 mice/group. *P<0.05 vs. control group.

Fig.3 PM2.5 exposure inhibits the expression and activity of SIRT2 and promotes the expression of phosphorylated and acetylated p65 and the activation of iNOS. (A) Representative immunoblots of SIRT2, p-p65, ace-p65, p65, and iNOS detected by Western blot analysis as described. The levels of SIRT2 (B), the ratio of p-p65/p65 (C), the ratio of ace-p65/p65 (D), and iNOS (E) were analyzed. β-actin was used as a loading control. (F) The SIRT2 activities in the lungs were determined by using SIRT-Glo^TM Assay (n = 6 mice/group). Meanwhile, the levels of nuclear or cytoplasmic p65 were checked to assess the activity of NF-κB (G). Data are expressed as mean±SD. n = 5 independent experiments. *P<0.05 vs. control group.

Fig.4 SIRT2 KO aggravates airway inflammation and hyperresponsiveness induced by PM2.5. (A) HE staining, (C) PAS staining, and (E) Masson staining were used to assess the histological changes of the airway. (B, D, and F) Graphs represent the inflammation scores, the number of PAS-positive cells, and the area of collagen in the bronchial basement membrane. (G) The bronchial hyperresponsiveness to acetylcholine was monitored to calculate the Penh. (H–J) The total cell number, eosinophil, and neutrophil infiltration in BALF were determined as an indication of potential airway inflammation injury. (K–N) The levels of IL-4, IL-5, IL-6, and TNF-α in BALF were assessed by ELISA. Data are expressed as mean±SD. n = 6 mice/group. *P<0.05 vs. WT+ Air group, ^#P<0.05 vs. SIRT2 KO+ Air group, ^†P<0.05 vs. WT+ PM2.5 group.

Fig.5 SIRT2 KO promotes PM2.5-induced phosphorylation and acetylation of p65 and the expression of iNOS. (A) Representative Co-IP analysis of p65 in the lung tissue from WT and SIRT2 KO mice. (B) SIRT2 activities in the lungs (n = 6 mice/group). (C) Representative immunoblots of SIRT2, p-p65, ace-p65, p65, and iNOS were detected by Western blot analysis as described. (D) The levels of SIRT2, (E) the ratio of p-p65/p65, (F) the ratio of ace-p65/p65, and (G) iNOS were analyzed. Data are expressed as mean±SD. n = 5 independent experiments. *P<0.05 vs. WT+ Air group, ^#P<0.05 vs. SIRT2 KO+ Air group, ^†P<0.05 vs. WT+ PM2.5 group.

Fig.6 Triptolide alleviates PM2.5-induced airway inflammation and hyperresponsiveness. (A) Lung tissue slices were examined by HE staining, (B) PAS staining, and (C) Masson staining. (D) Graphs represent the inflammation scores, (E) the number of PAS-positive cells in the bronchial basement membrane, and (F) the area of collagen. (G) The sections were stained with DHE to evaluate and quantify pulmonary ROS generation. (H) Graphs represent the DHE intensity. (I) The bronchial hyperresponsiveness to acetylcholine was monitored to calculate the Penh. (J–L) The total cell number, eosinophil, and neutrophil infiltration in BALF were determined as an indication of potential airway inflammation injury. (M–P) The levels of IL-4, IL-5, IL-6, and TNF-α were assessed by ELISA. Data are expressed as mean±SD. n = 6 mice/group. *P<0.05 vs. WT+ Air group, **P<0.05 vs. SIRT2 KO+ Air group, ^#P<0.05 vs. WT+ PM2.5 group, ^##P<0.05 vs. SIRT2 KO+ PM2.5 group, ^†P<0.05 vs. WT+ PM2.5+ Triptolide group.

Fig.7 Triptolide inhibits the expression of phosphorylated and acetylated p65 and the activation of iNOS induced by PM2.5. (A) Representative Co-IP analysis of p65 in lung tissue from WT and SIRT2 KO mice. (B) The SIRT2 activities in the lungs were determined (n = 6 mice/group). (C) Representative immunoblots of SIRT2, p-p65, ace-p65, p65, and iNOS were detected by Western blot analysis as described. (D) The levels of SIRT2, (E) the ratio of p-p65/p65, (F) the ratio of ace-p65/p65, and (G) the levels of iNOS were analyzed. Data are expressed as mean±SD. n = 5 independent experiments. *P<0.05 vs. WT+ Air group, **P<0.05 vs. SIRT2 KO+ Air group, ^#P<0.05 vs. WT+ PM2.5 group, ^##P<0.05 vs. SIRT2 KO+ PM2.5 group, ^†P<0.05 vs. WT+ PM2.5+ Triptolide group.

Fig.8 Schematic showing that PM2.5-induced inhibition of SIRT2 exacerbates the activation of p65 and promotes airway inflammatory injury. PM2.5 exposure downregulates the expression and activity of SIRT2 in bronchial tissues and accordingly promotes the phosphorylation and acetylation of p65 and activation of NF-κB signaling. The transcriptional activation of p65 further increases the secretion of cytokines and inflammatory factors, including IL-4, IL-5, IL-6, and TNF-α. These inflammatory factors recruit inflammatory cells. This signal axis is the key mechanism leading to airway inflammation and mucus secretion. The activation of inflammation also accelerates tracheal stenosis and bronchial hyperresponsiveness. Collectively, SIRT2 plays a direct role in the regulation of p65 modification in PM2.5-induced airway inflammation injury.

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